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Novel Missense Mutations in the AXIN2 Gene Associated with Non a r c h i v e s o f o r a l b i o l o g y 5 9 ( 2 0 1 4 ) 3 4 9 – 3 5 3 Available online at www.sciencedirect.com ScienceDirect journal homepage: http://www.elsevier.com/locate/aob Novel missense mutations in the AXIN2 gene associated with non-syndromic oligodontia a,1 a,1 b a Singwai Wong , Haochen Liu , Baojing Bai , Huaiguang Chang , c,d e a, a, Hongshan Zhao , Yixiang Wang , Dong Han **, Hailan Feng * a Department of Prosthodontics, Peking University School and Hospital of Stomatology, Beijing, China b Department of Prosthodontics, Beijing Stomatology Hospital, Beijing, China c Department of Medical Genetics, Peking University Health Science Center, Beijing, China d Peking University Center for Human Disease Genomics, Peking University Health Science Center, Beijing, China e Central Laboratory, Peking University School and Hospital of Stomatology, Beijing, China a r t i c l e i n f o a b s t r a c t Article history: Objective: Oligodontia, which is the congenital absence of six or more permanent teeth Accepted 23 December 2013 excluding third molars, may contribute to masticatory dysfunction, speech alteration, aesthetic problems and malocclusion. To date, mutations in EDA, AXIN2, MSX1, PAX9, Keywords: WNT10A, EDAR, EDARADD, NEMO and KRT 17 are known to associate with non-syndromic oligodontia. The aim of the study was to search for AXIN2 mutations in 96 patients with non- Non-syndromic oligodontia syndromic oligodontia. Mutation screening AXIN2 Design: We performed mutation analysis of 10 exons of the AXIN2 gene in 96 patients with isolated non-syndromic oligodontia. Results: We identified two novel missense mutations (Exon 3 c.923C > T and Exon 11 c.2490G > C) in two patients. One mutation (c.923C > T) results in a Thr308Met substitution and the other mutation (c.2490G > C) results in a Met830Ile substitution. Conclusions: This is the first report indicating that mutations in AXIN2 are responsible for oligodontia in the Chinese population. Our findings indicate that AXIN2 can be regarded as a candidate gene for mutation detection in individuals with non-syndromic oligodontia in the Chinese population. # 2014 Elsevier Ltd. All rights reserved. affect between 0.08% and 0.16% of humans in Scandinavian 1. Introduction 1,2 countries. It can contribute to masticatory dysfunction, 3 speech alteration, aesthetic problems and malocclusion. Oligodontia which is the congenital absence of six or more Oligodontia may present as part of a syndrome; however, permanent teeth excluding third molar, has been reported to the isolated, non-syndromic form is more common. * Corresponding author at: Department of Prosthosdontics, School and Hospital of Stomatology, Peking University, 22 Zhongguancun Nandajie, Haidian District, Beijing 100081, China. Tel.: +86 10 82195232. ** Corresponding author at: Department of Prosthosdontics, School and Hospital of Stomatology, Peking University, 22 Zhongguancun Nandajie, Haidian District, Beijing 100081, China. Tel.: +86 10 82195322. E-mail addresses: [email protected] (D. Han), [email protected], [email protected] (H. Feng). 1 These authors contributed equally to this work. Abbreviations: AXIN2, axis inhibition protein 2; EDA, ectodysplasin A; MSX1, msh homeobox 1; PAX9, paired box 9; WNT10A, wingless- type MMTV integration site family member 10a; EDAR, ectodysplasin A receptor; EDARADD, EDAR-associated death domain; NEMO, nuclear factor-kappaB essential modulator; KRT 17, keratin 17; Dkk1, Dickkopf-related protein 1; Lef1, lymphoid enhancer-binding factor 1. 0003–9969/$ – see front matter # 2014 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.archoralbio.2013.12.009 350 a r c h i v e s o f o r a l b i o l o g y 5 9 ( 2 0 1 4 ) 3 4 9 – 3 5 3 Although several potential and verified environmental PCR conditions are available upon request. SeqMan Pro genetic factors have been identified in tooth agenesis, genetic defects analysis software (DNASTAR, Madison, USA) was used for 4 play a major role in the aetiology. To date, mutations in EDA, sequencing analysis. AXIN2, MSX1, PAX9, WNT10A, EDAR, EDARADD, NEMO and KRT 5–14 17are known to cause isolated oligodontia. Reports of the 2.4. Conservation analysis analysis of AXIN2 mutations in isolated tooth agenesis are rare in comparison with investigations of other causative genes; Multiple species amino acid sequence alignment analysis of therefore, in this study, we focused on the role of the AXIN2 the AXIN2 protein (NP_004646.3) was carried out using gene in isolated oligodontia. ClustalX 2.1 and Jalview. The Axin2 sequences of nine Axin2 is a feedback inhibitor in the canonical Wnt pathway, different vertebrate species were obtained from ENSEMBL. 15 involving targeted degradation of free b-catenin. Somatic AXIN2 mutations have been described in a number of human 16,17 cancers, including skin, gastrointestinal, liver and ovarian. 3. Results Germline AXIN2 mutations were first identified in a Finnish four-generation family presenting with familial oligodontia and 3.1. Clinical details a predisposition to colorectal cancer with complete pene- 18 trance. Subsequently, AXIN2 mutations were reported in Oral examinations of all participants were performed by 7,19 patients with syndromic or non-syndromic tooth agenesis. prosthodontists to record dentition status, as well as the Therefore, we selected AXIN2 as a candidate gene for shapes and sizes of residual teeth. Panoramic radiographs screening oligodontia patients in the Chinese population. In were taken to confirm the diagnosis and the number of this study, we identified two novel missense mutations in two missing teeth. Phenotypic characteristics of scalp and body subjects with non-syndromic oligodontia, both of which were hair, skin, nails, tolerance to heat, and ability to sweat were located in highly conservative region of the encoded protein. examined through observation, palpation, and inquiry. All participants reported normal sweating and lachrymal secre- tions. None of the participants reported dry mouth sensations, 2. Materials and methods intolerance to heat, or susceptibility to respiratory tract 2.1. Participants Ninety-six non-consanguineous participants diagnosed with isolated oligodontia were recruited from the Department of Prosthodontics, Peking University School and Hospital of Stomatology and the Department of Prosthodontics, Beijing Stomatological Hospital (China). A total of 200 normal volunteers without tooth agenesis (100 males and 100 females) were selected as control individuals. This study was approved by the Institutional Review Board of Peking University School and Hospital of Stomatology (No. IRB0001052-07068). All of participants provided written consent to DNA sequencing analysis and the reproduction of radiographs. 2.2. DNA extraction Genomic DNA was extracted from peripheral blood lympho- cytes and buccal epithelial cells of the oligodontia patients and their relatives using the Biotek DNA minikit (Biotek, Beijing, China) according to manufacturers’ instructions. Genomic DNA was extracted from the buccal epithelial cells of normal volunteers using swab DNA mini kit (Tiangen, Beijing, China) according to manufacturers’ instructions. 2.3. Mutation detection Fig. 1 – Clinical characteristics of non-syndromic The entire coding region and intron–exon junctions of AXIN2 oligodontia patients with AXIN2 mutations. (A) Schematic genes were amplified by polymerase chain reaction (PCR) with presentation of congenitally missing teeth in two (35# and Amplitaq Gold 360 Master Mix (Applied Biosystems, Foster 49#) non-syndromic oligodontia patients with AXIN2 City, USA). The PCR products were sent to Sangon Biotech mutations. The missing teeth are represented by a filled Company (Beijing, China) for direct sequencing using a square. Max, maxillary; Mand, mandibular. (B) Panoramic BigDye terminator v3.1 (Applied Biosystems) and a 3730 radiograph of Patient 35#. (C) Panoramic radiograph of DNA sequencer (Applied Biosystems). Primer sequences and Patient 49#. * indicates the position of missing teeth. a r c h i v e s o f o r a l b i o l o g y 5 9 ( 2 0 1 4 ) 3 4 9 – 3 5 3 351 infections. The participants had hair on the body and scalp, and their facial features, skin, and nails were observed to be normal. Patient 35# was a 12-year-old female in good health. Clinical and radiographic examinations revealed that, in addition to retained deciduous teeth, the patient was missing a total of 12 permanent teeth, including five incisors and seven premolars (Fig. 1A and B). This individual had no other ectodermal abnormalities or systemic disease. There was no history of tooth agenesis or cancer in either of the maternal or paternal ancestries. Patient 49# was a 22-year-old female with normal appear- ance. The clinical and radiographic examination of Patient 49# revealed oligodontia with agenesis of 12 teeth, including all the second premolars, as well as all upper incisors and two lower incisors (Fig. 1A and C). All other ectodermal organs appeared normal and the patient reported no family history of tooth agenesis or cancer. Fig. 2 – Sequence analyses of the AXIN2 gene in two patients with congenital non-syndromic oligodontia. (A) A 3.2. Mutation analysis de novo heterozygous mutation c.923C > T was detected in Patient 35#. (B) A heterozygous mutation c.2490G > C was In this study, mutation analysis of exons 2–11 of the AXIN2 detected in Patient 49#. gene was conducted in 96 patients with non-syndromic oligodontia. Two novel missense mutations, c.923C > T (p.Thr308Met) and c.2490G > C (p.Met830Ile), were identified in two patients (35# and 49#). For Patient 35#, the nucleotide sequence showed a (c.2490G > C) of the coding sequence in exon 11 of AXIN2, heterozygous C to T transition at nucleotide 923 (c.923C > T) which results in the substitution of Met at residue 830 to Ile of the coding sequence in exon 3 of AXIN2, which results in the (Fig. 2B). The participant’s mother did not carry the substitution of Thr at residue 308 to Met (Fig.
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